Divergent synthesis of chiral spiro (isoxazole-isoxazoline) hybrid ligands

Article abstract of DOI:10.1016/j.tetasy.2008.10.019

An efficient synthetic method for chiral (isoxazole-isoxazoline) ligands based on a spiro[4.5]decane framework has been developed. A variety of enantiomerically pure ligands were readily prepared via the Suzuki-Miyaura coupling. The palladium complexes of

Full text of DOI:10.1016/j.tetasy.2008.10.019

Tetrahedron: Asymmetry 19 (2008) 2492–2496
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Divergent synthesis of chiral spiro (isoxazole–isoxazoline) hybrid ligands
*
Kazuhiro Takenaka, Shuhei Nakatsuka, Tetsuya Tsujihara, Priti S. Koranne, Hiroaki Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2008
Accepted 20 October 2008
An efficient synthetic method for chiral (isoxazole–isoxazoline) ligands based on a spiro[4.5]decane
framework has been developed. A variety of enantiomerically pure ligands were readily prepared via
the Suzuki–Miyaura coupling. The palladium complexes of these ligands have proven to be effective cat-
alysts for the asymmetric Wacker-type cyclization of an alkenyl alcohol.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the chiral spiro hybrid ligands 1. Herein, we report an efficient
strategy for the preparation of chiral spiro hybrid ligands 1, in
The development of novel chiral ligands is one of the most
important tasks in the area of asymmetric catalysis. The spirocyclic
framework has received considerable attention as a promising chi-
ral skeleton over the past decade because ligands containing such a
unique backbone are expected to exhibit unusual reactivity and
selectivity.1,2 For instance, great effort has been made toward the
preparation of chiral spiro phosphorus ligands by Zhou et al.1,3
They demonstrated the usefulness of these ligands for catalytic
asymmetric reactions in which known chiral ligands did not pro-
vide any successful results. We have also been investigating the
utility of chiral spiro ligands, for example, spiro bis(isoxazoline)s
(SPRIXs),4 which promote Pd-catalyzed asymmetric cyclization
reactions.4b–d
which Pd-catalyzed cross-coupling reaction of a key precursor for
1 is involved as the final step.
spiro[4.5]decane skeleton
H
R2
N N
R3
R1
chiral spiro hybrid ligands 1
O
O
2. Results and discussion
In this class of chiral ligands, C2-symmetric spiro scaffolds
occupying a prominent position have been developed. By contrast,
we have recently succeeded in the development of novel chiral
(isoxazole–isoxazoline) hybrid ligands 1 bearing an unsymmetrical
spiro[4.5]decane skeleton.5 These hybrid ligands were found to be
useful in the Pd-catalyzed enantioselective tandem cyclization of a
dialkenyl alcohol producing a peculiar bicyclic product. A combina-
tion of the isoxazole and the isoxazoline coordination sites may
contribute to the particular reactivity in the catalysis. It is possible
that the weak donor abilities of both the heterocycles built on the
fairly rigid scaffold keep the strong Lewis acidity of the ‘naked’ Pd
metal almost intact, allowing high activity of the catalysts.
Although these hybrid ligands display specific properties, synthetic
limitation has emerged as a serious problem. Since a multistep pro-
cess is indispensable for the preparation of all the ligands,5 much
time can be spent on arrangements for a wide variety of chiral
spiro ligands. This problem therefore imposes a restriction on the
development of new catalytic enantioselective reactions using
2.1. Design and preparation of a key precursor
The previous results imply two structural pieces of information
for the design of useful chiral ligands.5 One is the importance of
two i-Pr groups on the isoxazoline ring (substituents R2 and R3)
to create an effective asymmetric environment. The other is the
R1 on the isoxazole ring that significantly affects not only the
enantioselectivity but also the catalytic activity. As a result, we
designed 3-bromo-30,30-diisopropyl-30,3a0,40,5,50,6-hexahydro-4H-
spiro[2,1-benzisoxazole-7,60-cyclopenta[c]isoxazole] 1a as a key
synthetic precursor (Scheme 1). The bromo group at the 3-position
of the isoxazole ring can be replaced with various functional
cross-coupling
reaction
H
H
i-Pr
i-Pr
i-Pr
i-Pr
N N
N N
R
O
Br
O
O
O
a library of ligands 1
1a
* Corresponding author. Tel.: +81 6 6879 8465; fax: +81 6 6879 8469.
E-mail address: sasai@sanken.osaka-u.ac.jp (H. Sasai).
Scheme 1. Divergent synthetic strategy towards chiral spiro hybrid ligands 1.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.019

K. Takenaka et al. / Tetrahedron: Asymmetry 19 (2008) 2492–2496
2493
groups via cross-coupling reactions, which leads to the facile con-
struction of a library of chiral spiro hybrid ligands 1.
spiro hybrid ligands (Table 1). As expected, the key precursor 1a re-
acted with 1.5 equiv of phenylboronic acid in the presence of
K2CO3 and Pd(PPh3)4 catalysts in aqueous THF at reflux tempera-
ture to give the enantiomerically pure spiro ligand 1b with a phe-
nyl group in 94% yield (entry 1). Similarly, the spiro hybrid ligands
1c–g with a para-substituted phenyl group were obtained in good
to excellent yields (entries 2–6). It was also feasible to introduce a
naphthyl group onto the isoxazole ring: compounds 1h and 1i
were obtained in 43% and 27% yields, respectively (entries 7 and
8). The sterically more demanding 9-anthrylboronic acid, however,
was inapplicable to this synthetic method under the same reaction
conditions. It was found that the reaction progressed when 1,2-
dimethoxyethane (DME) as the solvent and Ba(OH)2ꢀ8H2O as the
base were used.10 Thus, a mixture of the key precursor 1a, 9-ant-
hrylboronic acid (1.5 equiv), and Ba(OH)2ꢀ8H2O (2 equiv) in aque-
ous DME was refluxed for 24.5 h to furnish the spiro hybrid
ligand 1j possessing a 9-anthryl group in 57% yield (entry 9). Under
these conditions, the reactions of 1a with less reactive boronic
acids (2,6-xylyl-, 2-biphenyl-, 2-trifluoromethylphenyl-, and 3,5-
bis(trifluoromethyl)phenyl-boronic acids) were carried out to give
the corresponding spiro hybrid ligands 1k–n in excellent yields
(entries 10–13).
The racemic compound 1a was readily prepared from diethyl
malonate in 7 steps via the known dioxime 25 (Scheme 2). Thus
treatment of 2 with N-bromosuccinimide (NBS) in the presence
of a catalytic amount of AgNO3 in DMF gave the dioxime with a
brominated acetylene 3 in 77% yield.6 The following double nitrile
oxide cycloaddition proceeded smoothly to afford ca. 2:1 diaste-
reomeric mixture of 1a and 10a in 63% combined yield.7 The desired
isomer 1a was isolated by column chromatography on silica gel
and identified by NMR, ESI-MS, and elemental analysis.
i-Pr
R
i-Pr
EtO
EtO
H
H
O
O
N
N
(5 steps)
HO
a
OH
2
: R = H
3: R = Br
R*
N N
H
R*
N N
H
S*
R*
b
i-Pr
i-Pr
+
i-Pr
i-Pr
Table 1
Preparation of enantiomerically pure aryl-substituted spiro hybrid ligandsa
Br
O
Br
O
O
O
RB(OH)2
1a
1'a
rac-
rac-
H
H
Pd(PPh3)4
i-Pr
i-Pr
i-Pr
i-Pr
Scheme 2. Synthesis of the key precursor 1a. Reagents and conditions: (a) AgNO3
(10 mol %), NBS (1.3 equiv), DMF, rt, 22.5 h, 77%; (b) aq NaOCl (1.2 equiv), CH2Cl2,
0 °C then rt, 17 h, 42% for 1a, 20% for 10a.
K2CO3
N N
N N
Br
O
R
O
aq. THF, reflux
O
O
1a
1
Once the key precursor was obtained in an enantiomerically
pure form, the tedious resolution for each ligand normally required
was not needed: this is the marked advantage in the present meth-
od. Gratifyingly, enantiomerically pure 1a was obtained by optical
resolution using HPLC equipped with a preparative-scale chiral sta-
tionary phase column (Daicel Chiralpak AD). In addition, single
crystals of one of the enantiomers (2nd peak in the HPLC chart)
were obtained from a solution of the enantiopure 1a in Et2O/hex-
ane by slow evaporation. The structure of 1a was unambiguously
established by X-ray analysis (Fig. 1).8 The distance between the
two nitrogen atoms is 3.62 Å, which is nearly identical to that of
the previously reported spiro hybrid ligand (3.71 Å).5 The X-ray
diffraction study also revealed the absolute configuration of the
enantiomer to be (R,S).9
Entry
R
Time (h)
Yieldb (%)
Absolute
configuration
1
2
3
4
5
6
7
8
Ph
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
24
24
22
22
21
14
24
24
24.5
30
32.5
21
94
92
99
78
97
99
43
27
57
95
97
97
89
(S,R)
(R,S)
(S,R)
(S,R)
(S,R)
(S,R)
(S,R)
(S,R)
(R,S)
(S,R)
(R,S)
(R,S)
(S,R)
4-MeOC6H4
4-MeSC6H4
4-Me2NC6H4
4-MeOCOC6H4
4-FC6H4
1-Naphthyl
2-Naphthyl
9-Anthryl
9c
10c
11c
12c
13c
2,6-Xylyl
2-Biphenyl
2-CF3C6H4
3,5-(CF3)2C6H3
25.5
a
All reactions were performed with 1a, arylboronic acid (1.5 equiv), K2CO3
(2 equiv), and Pd(PPh3)4 (5–10 mol %) at reflux in aqueous THF.
b
Isolated yield.
c
DME and Ba(OH)2ꢀ8H2O were used instead of THF and K2CO3, respectively.
Since the Suzuki–Miyaura reaction realized
a divergent
synthetic protocol for chiral spiro hybrid ligands (vide supra), other
Pd-catalyzed cross-coupling reactions of 1a were examined. To our
disappointment, the Mizoroki–Heck, the Sonogashira–Hagihara,
and the Buchwald–Hartwig reactions did not work, instead result-
ing in the formation of a complex mixture or the quantitative
recovery of 1a.
2.3. Utility of spiro hybrid ligands for the Pd-catalyzed
asymmetric Wacker-type cyclization
Figure 1. ORTEP drawing of (R,S)-1a. One molecule of two independent molecules
in a unit cell is presented. The hydrogen atoms are omitted for clarity. Selected
distance: Nꢀ ꢀ ꢀN = 3.62 Å.
The chiral spiro hybrid ligands have proven to be effective for
the asymmetric Wacker-type cyclization.5 To explore the utility
of the novel ligands 1, we elected to study the Pd-catalyzed asym-
metric oxidative cyclization of an alkenyl alcohol affording pyran
derivatives,4b which are ubiquitous substructures among biologi-
cally active molecules. The reaction of 2-benzyl-2-(3-methyl-2-
2.2. Divergent synthesis of various chiral spiro ligands
With the enantiomerically pure 1a in hand, we applied the
Suzuki–Miyaura cross-coupling to the divergent synthesis of chiral

2494
K. Takenaka et al. / Tetrahedron: Asymmetry 19 (2008) 2492–2496
butenyl)-1,3-propanediol 4 was carried out in the presence of
10 mol % of Pd(OCOCF3)2 and 12 mol % of chiral ligand in CH2Cl2
to give 6-endo cyclized product 5. Representative results are sum-
marized in Table 2. The key precursor over the course of ligand
synthesis, 1a, itself acted as a chiral ligand. Thus, a catalyst pre-
pared in situ from the Pd salt and 1a promoted the reaction at
25 °C, leading to the formation of 5 in 62% yield with 48% ee (entry
1). While the loss of catalytic activity was observed in the reaction
employing the phenyl-substituted ligand 1b, the enantioselectivity
of 5 was slightly increased to 56% ee (entry 2). No appreciable
effects were detected upon changing the electronic factor of the
substituted phenyl ring (entries 3–6). The use of the bulkier
1-naphthyl ligand 1h improved neither the chemical yield nor
the enantioselectivity (entry 7). The ligands showing a high
acceleration in the reaction at 25 °C, 1j–n, were subjected to fur-
ther investigation at lower temperatures (entries 8–12). Among
them, ligand 1l carrying a 2-biphenyl group displayed the highest
selectivity at 15 °C while maintaining catalytic activity (69% yield
with 82% ee, entry 10). This result was comparable to that obtained
with 1o having a t-Bu group on the isoxazole ring, the best ligand
in the previous report,5 suggesting the high efficiency of the pres-
ent method for the preparation of useful chiral ligands (entry 13).
ligands to asymmetric catalysis are currently underway and will be
reported in due course.
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere using
standard Schlenk techniques. All NMR spectra were recorded in
CDCl3 at 25 °C on JEOL JNM-EX270 (270 MHz for 1H, 67.7 MHz
for 13C). Chemical shifts are reported d in ppm referenced to an
internal Me4Si standard for 1H NMR. Chemical shifts of 13C NMR
are given relative to CDCl3 (d 77.0). IR spectra were obtained with
Perkin–Elmer System 200 FT-IR instrument. Optical rotations were
measured with JASCO P-1030 polarimeter. GC analysis was carried
out on a GL Sciences GC-4000 with a capillary column, InertCap 5.
Enantiomeric excesses were determined by HPLC analysis
equipped with a chiral stationary phase column (Daicel Chiralpak
AD). Mass spectra were recorded on JEOL JMS-T100LC (ESI-MS).
Melting points were measured with Yanaco micro melting point
apparatus MP-S9, and were uncorrected.
4.2. Materials
Table 2
Pd-catalyzed asymmetric oxidative cyclization of 4a
CH2Cl2 and DMF were distilled from CaH2 prior to use.
Anhydrous THF was purchased from Kanto Chemicals and used
without any purification. p-Benzoquinone was purified by subli-
mation under vacuum. Column chromatography was performed
Pd(OCOCF3)2
Ligand
Bn
OH
Bn
OH
p-benzoquinone
HO
O
CH2Cl2
on Merck Silica Gel 60 (63–200 l
m). Pd(PPh3)4,11 2-(pent-4-yn-1-
4
5
yl)-2-(4-isopropyl-5-methylhex-3-en-1-yl)-malonaldehyde diox-
ime 2,5 and 2-benzyl-2-(3-methyl-2-butenyl)-1,3-propanediol 44b
were prepared according to the reported procedures. All other
chemicals were purchased from commercial suppliers and used
as received.
Entry
Ligand
Temp. (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1e
1f
1g
1h
1j
1k
1l
1m
1n
1oe
25
25
25
25
25
25
25
15
15
15
15
15
15
39
31
31
38.5
31
31
34
48
48
48
48
48
48
62
48d
42
56
41d
44
55d
54
72
69
73
65
61
48
56
71
67
63
68
55
63
66
82
70
74
78
4.3. Preparation of 2-(5-bromopent-4-yn-1-yl)-2-(4-isopropyl-
5-methylhex-3-en-1-yl)-malonaldehyde dioxime 3
To a solution of 2 (2.62 g, 8.55 mmol) in dry DMF (26 mL) were
added N-bromosuccinimide (1.98 g, 11.1 mmol) and AgNO3
(0.146 g, 0.855 mmol), which was stirred at room temperature
for 22.5 h. After the reaction was quenched by the addition of ethyl
acetate and H2O, the mixture was extracted with ethyl acetate. The
organic layer was dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography on silica gel (hexane/ethyl acetate = 7/1–6/
1) to give 3 (2.55 g, 77%) as a white solid. Mp: 52–55 °C. 1H
NMR: d 0.98 (d, J = 6.9 Hz, 6H), 0.99 (d, J = 6.9 Hz, 6H), 1.50–1.58
(m, 2H), 1.64–1.71 (m, 2H), 1.74–1.80 (m, 2H), 1.99–2.08 (m,
2H), 2.19–2.31 (m, 3H), 2.72 (sept, J = 6.9 Hz, 1H), 5.02 (t,
J = 7.2 Hz, 1H), 7.42 (s, 2H). 13C NMR: d 20.1, 21.3, 21.9, 23.0,
24.7, 28.7, 29.4, 34.9, 36.9, 38.5, 45.7, 79.5, 119.7, 152.2, 153.7. IR
(KBr): 3272, 2962, 2869, 1887, 1731, 1461, 1363, 1301, 1103,
942, 717 cm–1. MS (ESI): m/z 407, 409 ([M+Na]+).
a
All reactions were performed in CH2Cl2 under an argon atmosphere. The ratio of
4 (mol)/Pd (mol)/ligand (mol)/p-benzoquinone (mol)/CH2Cl2 (L) = 1.0/0.1/0.12/4.0/
4.0.
b
GC yield using hexamethylbenzene as an internal standard unless otherwise
noted.
c
Determined by Daicel Chiralpak AD column, hexane/2-propanol (9/1).
d
NMR yield using 1,4-dimethoxybenzene as an internal standard.
For the structure of ligand 1o, see Scheme 1 (R = t-Bu).5
e
3. Conclusion
In conclusion, we have developed a new efficient synthetic
method toward chiral (isoxazole–isoxazoline) hybrid ligands based
on an unsymmetrical spiro[4.5]decane backbone. A variety of ena-
tiomerically pure spiro hybrid ligands were successfully synthe-
sized via the Suzuki–Miyaura cross-coupling reaction of the key
precursor, which contained a bromo group at the 3-position of
the isoxazole ring. Single crystal X-ray analysis of the key precursor
elucidated the absolute configuration as well as the molecular
structure. The chiral spiro hybrid ligands were effective ligands
for the Pd-catalyzed asymmetric oxidative cyclization of an alkenyl
alcohol. Further investigation of the present methodology for the
preparation of novel chiral ligands and applications of the resulting
4.4. Preparation of 3-bromo-30,30-diisopropyl-30,3a0,40,5,50,6-
hexahydro-4H-spiro[2,1-benzisoxazole-7,60-cyclopenta-
[c]isoxazole] (1a and 10a)
To a solution of 3 (2.55 g, 6.62 mmol) in CH2Cl2 (13 mL) was
added aq NaOCl (>5.0% chlorine, 10.4 mL, 8.22 mmol) at 0 °C,
which was stirred at room temperature for 17 h. The reaction mix-
ture was diluted with water and extracted with CH2Cl2. The organ-
ic layer was washed with brine and dried over anhydrous Na2SO4.
After removal of the desiccant and volatiles, the crude product was

K. Takenaka et al. / Tetrahedron: Asymmetry 19 (2008) 2492–2496
2495
purified by column chromatography on silica gel (hexane/
4.5.4. (S,R)-1e
acetone = 80/1–60/1) to give 1a (1.06 g, 42%) and 10a (0.500 g,
20%) as white solids.
78% yield. Yellow solid. Mp: 215 °C. ½a D23
ꢃ
¼ ꢁ157:9 (c 0.615,
CHCl3). 1H NMR: d 0.92–1.11 (m, 12H), 1.73–2.70 (m, 10H), 2.87–
3.05 (m, 8H), 3.80 (dd, J = 11.4 Hz, J = 8.2 Hz, 1H), 6.74 (d,
J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H). 13C NMR: d 17.8, 18.4, 18.7,
18.8, 18.8, 20.4, 20.9, 24.0, 31.3, 31.8, 34.9, 39.4, 40.2, 45.0, 55.8,
95.6, 107.3, 111.9, 127.0, 150.5, 163.5, 165.1, 172.9. IR (KBr): 3757,
2967, 1607, 1487, 1367, 820 cmꢁ1. MS (ESI): m/z 444 ([M+Na]+).
Compound 1a: Mp: 135–138 °C. 1H NMR: d 0.87–1.01 (m, 12H),
1.73–1.97 (m, 6H), 2.15–2.37 (m, 4H), 2.49–2.56 (m, 1H), 2.77–2.84
(m, 1H), 3.75 (dd, J = 11.2 Hz, J = 8.1 Hz, 1H). 13C NMR: d 17.7, 18.3,
18.6, 18.6, 18.7, 19.6, 23.9, 31.3, 31.7, 34.9, 39.3, 44.2, 55.4, 95.9,
114.2, 136.9, 166.3, 172.1. IR (KBr): 3850, 2976, 1404, 939,
850 cmꢁ1. MS (ESI): m/z 403, 405 ([M+Na]+). Anal. Calcd for
C18H25BrN2O2: C, 56.70; H, 6.61; N, 7.35. Found: C, 56.70; H,
6.65; N, 7.30.
4.5.5. (S,R)-1f
97% yield. White solid. Mp: 159–161 °C. ½a D23
¼ ꢁ157:7 (c 0.615,
ꢃ
The enantiomers were separated by using Daicel Chiralpak AD
CHCl3). 1H NMR: d 0.92–1.09 (m, 12H), 1.75–2.50 (m, 9H), 2.65–
2.77 (m, 1H), 2.88–2.98 (m, 2H), 3.81 (dd, J = 11.1 Hz, J = 8.3 Hz,
1H), 3.94 (s, 3H), 7.79 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H).
13C NMR: d 17.8, 18.4, 18.7, 18.8, 20.2, 21.0, 24.0, 31.3, 31.8, 34.6,
39.4, 44.8, 52.3, 55.6, 95.9, 111.8, 125.5, 130.0, 130.3, 132.3,
161.5, 165.6, 166.3, 172.6. IR (KBr): 3752, 2971, 1725, 1440,
1284, 1112, 756 cmꢁ1. MS (ESI): m/z 459 ([M+Na]+).
[2 cm
U
ꢂ 25 cm, hexane/i-PrOH = 20/1, 4.0 mL/min], 17 min for
(S,R)-1a, 34.5 min for (R,S)-1a). (S,R)-1a: ½a D19
¼ ꢁ175:0 (c 0.500,
ꢃ
CHCl3). (R,S)-1a: ½a D19
¼ þ177:3 (c 0.500, CHCl3).
ꢃ
Compound 10a: 1H NMR: d 0.85–1.00 (m, 12H), 1.72–1.99 (m,
5H), 2.10–2.68 (m, 7H), 4.07 (t, J = 9.7 Hz, 1H). 13C NMR: d 17.2,
17.8, 18.1, 18.6, 18.8, 20.0, 21.1, 31.5, 31.5, 33.3, 39.3, 43.5, 54.6,
95.9, 114.0, 136.8, 166.1, 171.0. IR (KBr): 3851, 2956, 1607, 1403,
851 cmꢁ1. MS (ESI): m/z 403, 405 ([M+Na]+).
4.5.6. (S,R)-1g
99% yield. White solid. Mp: 159–161 °C. ½a D23
¼ ꢁ153:9 (c 0.730,
ꢃ
CHCl3). 1H NMR: d 0.92–1.09 (m, 12H), 1.74–2.50 (m, 9H), 2.59–
2.71 (m, 1H), 2.85–2.94 (m, 2H), 3.81 (dd, J = 11.4 Hz, J = 8.0 Hz,
1H), 7.14 (virtual t, J = 8.7 Hz, 2H), 7.70 (dd, J = 8.9 Hz, J = 5.3 Hz,
2H). 13C NMR: d 16.0, 17.8, 18.3, 18.7, 18.7, 20.2, 20.8, 24.0, 31.3,
31.8, 34.7, 39.4, 44.8, 55.6, 95.8, 109.8 (d, J = 1.1 Hz), 115.9 (d,
J = 21.9 Hz), 124.9 (d, J = 3.5 Hz), 127.8 (d, J = 8.4 Hz), 161.8, 162.9
(d, J = 249 Hz), 165.4, 172.7. IR (KBr): 3852, 2971, 1515, 1445,
1240, 840 cmꢁ1. MS (ESI): m/z 419 ([M+Na]+).
4.5. General procedure for the Suzuki–Miyaura cross-coupling
reaction
To a solution of 1a (38.1 mg, 0.100 mmol), arylboronic acid
(0.150 mmol), and Pd(PPh3)4 (11.6 mg, 0.0100 mmol) in dry THF
(1.4 mL) was added aqueous K2CO3 solution (1 M, 0.2 mL), which
was refluxed for the time indicated in Table 1. After being cooled
to room temperature, the reaction mixture was poured into
aqueous HCl (1 M), and then extracted with ethyl acetate. The
organic layer was dried over anhydrous Na2SO4, filtered, and
evaporated to dryness. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate) to produce
the arylated ligand.
4.5.7. (S,R)-1h
43% yield. White solid. Mp: 57–63 °C. ½a D24
¼ ꢁ138:2 (c 0.455,
ꢃ
CHCl3). 1H NMR: d 0.94–1.15 (m, 12H), 1.81–2.09 (m, 6H), 2.26–
2.55 (m, 4H), 2.63–2.71 (m, 1H), 2.99 (ddd, J = 12.0 Hz, J = 7.3 Hz,
J = 2.0 Hz, 1H), 3.84 (dd, J = 11.3 Hz, J = 8.2 Hz, 1H), 7.51–7.64 (m,
4H), 7.87–7.96 (m, 2H), 8.03–8.07 (m, 1H). 13C NMR: d 17.8, 18.4,
18.7, 18.8, 20.2, 20.3, 23.9, 31.4, 31.8, 35.2, 39.5, 45.0, 55.6, 95.8,
112.5, 124.9, 125.7, 125.8, 126.2, 126.9, 127.6, 128.3, 130.2,
130.7, 133.6, 163.9, 164.9, 172.8. IR (KBr): 3851, 2961, 1456,
1393, 777 cmꢁ1. MS (ESI): m/z 451 ([M+Na]+).
4.5.1. (S,R)-1b
94% yield. White solid. Mp: 209–213 °C. ½a D22
¼ ꢁ185:5 (c 0.605,
ꢃ
CHCl3). 1H NMR: d 0.93–1.10 (m, 12H), 1.75–2.53 (m, 9H), 2.63–
2.75 (m, 1H), 2.89–2.99 (m, 2H), 3.81 (dd, J = 11.5 Hz, J = 8.1 Hz,
1H), 7.36–7.48 (m, 3H), 7.73 (dd, J = 8.2 Hz, J = 1.7 Hz, 2H). 13C
NMR: d 17.8, 18.4, 18.7, 18.8, 20.3, 20.9, 24.0, 31.3, 31.8, 34.8,
39.4, 44.9, 55.6, 95.8, 110.1, 125.8, 128.5, 128.7, 129.1, 147.8,
162.7, 165.4. IR (KBr): 2969, 2941, 1446, 1428, 1387, 769,
691 cmꢁ1. MS (ESI): m/z 401 ([M+Na]+).
4.5.8. (S,R)-1i
27% yield. White solid. Mp: 232–233 °C (decomposed).
½
a 2D3
ꢃ
¼ ꢁ87:1 (c 0.465, CHCl3). 1H NMR: d 0.86–1.12 (m, 12H),
1.83–2.54 (m, 9H), 2.74–3.11 (m, 3H), 3.83 (dd, J = 11.5 Hz,
J = 8.2 Hz, 1H), 7.51–7.54 (m, 2H), 7.84–7.93 (m, 4H), 8.19 (s, 1H).
13C NMR: d 17.8, 18.4, 18.7, 18.8, 20.3, 21.0, 24.0, 31.3, 31.8, 34.8,
39.5, 45.0, 55.7, 95.8, 110.4, 123.0, 125.5, 126.0, 126.6, 126.9,
127.7, 128.5, 128.5, 133.0, 133.2, 162.7, 165.5, 172.8. IR (KBr):
3749, 2940, 1427, 1387, 1267, 857, 817, 751 cmꢁ1. MS (ESI): m/z
451 ([M+Na]+).
4.5.2. (R,S)-1c
92% yield. White solid. Mp: 161–164 °C. ½a D21
¼ þ182:0 (c 0.500,
ꢃ
CHCl3). 1H NMR: d 0.92–1.10 (m, 12H), 1.66–2.70 (m, 10H), 2.87–
2.94 (m, 2H), 3.80 (dd, J = 11.4 Hz, J = 8.3 Hz, 1H), 3.84 (s, 3H),
6.96 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.9 Hz, 2H). 13C NMR: d 17.8,
18.4, 18.7, 18.8, 20.3, 20.8, 24.0, 31.3, 31.8, 34.8, 39.4, 44.9, 55.3,
55.7, 95.7, 108.6, 114.2, 121.4, 127.3, 160.1, 162.7, 165.3, 172.8.
IR (KBr): 3851, 2971, 2562, 1892, 1608, 1515, 1428, 1256, 1175,
1030, 834 cmꢁ1. MS (ESI): m/z 431 ([M+Na]+). Anal. Calcd for
C25H32N2O3: C, 73.50; H, 7.90; N, 6.86. Found: C, 73.29; H, 7.95;
N, 6.81.
4.5.9. (R,S)-1j
57% yield. Yellow solid. Mp: 100–104 °C. ½a D23
¼ þ124:5 (c
ꢃ
0.805, CHCl3). 1H NMR: d 0.96–1.19 (m, 12H), 1.81–2.58 (m,
11H), 3.05–3.13 (m, 1H), 3.88 (dd, J = 11.1 Hz, J = 8.2 Hz, 1H),
7.47–7.66 (m, 4H), 7.52–7.78 (m, 2H), 8.03–8.08 (m, 2H), 8.59 (s,
1H). 13C NMR: d 17.8, 18.4, 18.7, 18.8, 19.2, 20.1, 23.8, 31.5, 31.8,
35.3, 39.7, 44.7, 55.5, 95.9, 115.0, 121.6, 125.2, 125.4, 125.5,
125.7, 126.5, 127.1, 128.3, 128.6, 129.6, 130.6, 130.7, 130.9,
131.1, 162.5, 164.7, 172.6. IR (KBr): 3748, 2959, 2360, 1446,
739 cmꢁ1. MS (ESI): m/z 501 ([M+Na]+).
4.5.3. (S,R)-1d
99% yield. White solid. Mp: 137–140 °C. ½a D22
¼ ꢁ174:0 (c 0.500,
ꢃ
CHCl3). 1H NMR: d 0.92–1.10 (m, 12H), 1.73–2.71 (m, 13H), 2.87–
2.94 (m, 2H), 3.80 (dd, J = 11.4 Hz, J = 8.2 Hz, 1H), 7.29 (d,
J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H). 13C NMR: d 15.3, 17.8,
18.3, 18.7, 18.8, 20.2, 20.9, 23.9, 31.3, 31.8, 34.7, 39.4, 44.9, 55.6,
95.7, 109.7, 125.1, 126.0, 126.0, 140.3, 162.3, 165.4, 172.7. IR
(KBr): 3748, 1731, 1442 cmꢁ1. MS (ESI): m/z 447 ([M+Na]+).
4.5.10. (S,R)-1k
95% yield. White solid. Mp: 45–47 °C. ½a D24
¼ ꢁ140:8 (c 0.500,
ꢃ
CHCl3). 1H NMR: d 0.92–1.10 (m, 12H), 1.67–2.40 (m, 17H), 2.91–

2496
K. Takenaka et al. / Tetrahedron: Asymmetry 19 (2008) 2492–2496
2.98 (m, 1H), 3.81 (dd, J = 11.2 Hz, J = 8.2 Hz, 1H), 7.09 (d, J = 7.6 Hz,
2H), 7.24 (t, J = 7.6 Hz, 1H). 13C NMR: d 17.8, 18.4, 18.7, 19.1, 19.9,
20.2, 23.8, 31.5, 31.8, 35.2, 39.6, 44.6, 55.5, 95.7, 112.2, 127.1+127.3
(br, 3,5-ArC, due to the hindered rotation), 127.5, 129.6,
138.0+138.5 (br, 2,6-ArC, due to the hindered rotation), 164.1,
164.3, 172.4, signals for CH3 groups on the Ar ring could not be ob-
served. IR (KBr): 3749, 2962, 1635, 1447, 1386, 1268, 1118,
776 cmꢁ1. MS (ESI): m/z 429 ([M+Na]+).
4.96 min; 5, 10.97 min) or NMR analysis (1,4-dimethoxybenzene
was used as an internal standard). The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate = 7/1)
to afford product 5. The enantiomeric excess of the product was
determined by HPLC analysis using a chiral stationary phase
column (Daicel Chiralpak AD, hexane/i-PrOH = 9/1, flow
rate = 1.0 mL/min, k = 215 nm: 5.6 min and 6.9 min).
Acknowledgments
4.5.11. (R,S)-1l
97% yield. White solid. Mp: 57–58 °C. ½a D24
ꢃ
¼ þ158:1 (c 0.500,
This research was supported partially by a Grant-in-Aid for
Scientific Research on Priority Areas ‘Advanced Molecular Trans-
formation of Carbon Resources’ from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. We also thank to
the technical staff of the Materials Analysis Center of ISIR for their
assistance.
CHCl3). 1H NMR: d 0.90–1.10 (m, 12H), 1.25–1.58 (m, 4H), 1.72–
2.01 (m, 4H), 2.14–2.41 (m, 3H), 2.77–2.85 (m, 1H), 3.74 (dd,
J = 11.5 Hz, J = 8.1 Hz, 1H), 7.18–7.63 (m, 9H). 13C NMR: d 17.8,
18.4, 18.7, 18.8, 19.0, 20.0, 23.8, 31.3, 31.7, 35.0, 39.3, 45.0, 55.6,
95.6, 111.8, 126.9, 127.1, 127.2, 128.2, 128.8, 129.8, 130.2, 130.3,
140.2, 141.2, 164.0, 164.6, 172.7. IR (KBr): 3851. 2944, 1715,
1634, 1458, 1009, 701, 667 cmꢁ1. MS (ESI): m/z 477 ([M+Na]+).
References
4.5.12. (R,S)-1m
1. For a recent review, see: Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581.
2. (a) Chan, A. S. C.; Hu, W.; Pai, C.-C.; Lau, C.-P.; Jiang, Y.; Mi, A.; Yan, M.; Sun, J.;
Lou, R.; Deng, J. J. Am. Chem. Soc. 1997, 119, 9570; (b) Hu, W.; Yan, M.; Lau, C.-P.;
Yang, S. M.; Chan, A. S. C.; Jiang, Y.; Mi, A. Tetrahedron Lett. 1999, 40, 973; (c) Li,
X.; Yeung, C.-H.; Chan, A. S. C.; Lee, D.-S.; Yang, T.-K. Tetrahedron: Asymmetry
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Ebeling, G.; Gruber, A. S.; Burrow, R. A.; Dupont, J.; Lough, A. J.; Farrar, D. H.
Inorg. Chem. Commun. 2002, 5, 552; (f) Lait, S. M.; Parvez, M.; Keay, B. A.
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L.; Chan, A. S. C. Tetrahedron Lett. 2004, 45, 7379; (i) Guo, Z.; Guan, X.; Chen, Z.
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Zhou, Q.-L. Angew. Chem., Int. Ed. 2008, 47, 932 and references cited therein.
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Angew. Chem., Int. Ed. 2007, 46, 1275; (b) Yang, Y.; Zhu, S.-F.; Duan, H.-F.; Zhou,
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H.-F.; Xie, J.-H.; Qiao, X.-C.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2008,
47, 4351; (e) Li, S.; Zhu, S.-F.; Zhang, C.-M.; Song, S.; Zhou, Q.-L. J. Am. Chem. Soc.
2008, 130, 8584.
97% yield. White solid. Mp: 108–112 °C. ½a D24
¼ þ157:2 (c 0.500,
ꢃ
CHCl3). 1H NMR: d 0.92–1.09 (m, 12H), 1.74–2.33 (m, 6H), 2.22–
2.47 (m, 4H), 2.60–2.66 (m, 1H), 2.93 (dd, J = 12.9 Hz, J = 7.3 Hz,
1H), 3.81 (dd, J = 11.4 Hz, J = 8.1 Hz, 1H), 7.51–7.66 (m, 3H), 7.78
(d, J = 7.7 Hz, 1H). 13C NMR: d 17.8, 18.3, 18.7, 18.7, 19.2, 20.1,
23.9, 31.3, 31.7, 35.0, 39.4, 45.0, 55.7, 95.7, 112.9, 123.3 (q,
J = 273 Hz), 126.7 (q, J = 5.0 Hz), 126.7 (q, J = 4.0 Hz), 129.6 (q,
J = 31.4 Hz), 129.8, 131.3, 131.6, 161.4, 164.5, 172.6. IR (KBr):
3851, 2965, 1442, 1427, 1317, 1174, 1137, 1037, 771 cmꢁ1. MS
(ESI): m/z 469 ([M+Na]+).
4.5.13. (S,R)-1n
89% yield. Colorless oil. ½a D24
ꢃ
¼ ꢁ134:7 (c 0.500, CHCl3). 1H NMR:
d 0.92–1.09 (m, 12H), 1.75–2.51 (m, 9H), 2.68–2.80 (m, 1H), 2.88–
3.00 (m, 2H), 3.82 (dd, J = 11.3 Hz, J = 8.1 Hz, 1H), 7.89 (br s, 1H),
8.15 (br s, 2H). 13C NMR: d 17.7, 18.3, 18.7, 18.7, 20.0, 20.7, 24.0,
31.4, 31.8, 34.5, 39.4, 44.5, 55.6, 96.0, 112.6, 122.4 (sept, J = 3.8
Hz), 122.9 (q, J = 272 Hz), 125.6 (m), 130.3, 132.4 (q, J = 33.7 Hz),
159.5, 166.0, 172.5. IR (KBr): 3748, 2965, 2359, 1809, 1716, 1622,
1471, 1446, 1373, 1280, 1145, 899, 847, 807, 712, 700 cmꢁ1. MS
(ESI): m/z 537 ([M+Na]+).
4. (a) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1, 1795; (b) Arai, M. A.; Kuraishi,
M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907; (c) Shinohara, T.; Arai, M.
A.; Wakita, K.; Arai, T.; Sasai, H. Tetrahedron Lett. 2003, 44, 711; (d) Muthiah, C.;
Arai, M. A.; Shinohara, T.; Arai, T.; Takizawa, S.; Sasai, H. Tetrahedron Lett. 2003,
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K.; Sasai, H. Tetrahedron: Asymmetry 2007, 18, 919.
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3194; (b) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599.
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Kozlowski, M.; Lee, V. G.; Liu, E. C.-K.; Malley, M. F.; McMullen, D.; Mitchell, C.;
Moreland, S.; Murugesan, N.; Serafino, R.; Webb, M. L.; Zhang, R.; Hunt, J. T.
J. Med. Chem. 1995, 38, 1344.
4.6. Typical procedure for Pd-catalyzed oxidative cyclization of
2-benzyl-2-(3-methyl-2-butenyl)-1,3-propanediol 4
A solution of enantiopure ligand (0.012 mmol) and Pd(OCOCF3)2
(3.3 mg, 0.010 mmol) in CH2Cl2 (0.4 mL) was stirred at 25 °C for 2 h
under an argon atmosphere. To this solution were added p-benzo-
quinone (43.2 mg, 0.40 mmol) and 4 (23.4 mg, 0.100 mmol). The
reaction mixture was stirred at the indicated temperature, and
the reaction course was monitored by TLC. After completion, the
reaction mixture was filtered through a short pad of silica gel,
which was rinsed with ethyl acetate. The filtrate was concentrated
under reduced pressure. Product yield was determined by GC anal-
ysis (hexamethylbenzene was used as an internal standard,
TCOL = 180 °C, TINJ = 250 °C, TDET = 250 °C: hexamethylbenzene,
8. Crystal data: space group P21 (#4), a = 12.572(4) Å, b = 13.578(5) Å,
c = 10.927(2) Å, b = 106.58(2)°, V = 1787.8(9) Å3, Z = 4, Dcalcd = 1.417 g/cm3,
R = 0.0950 (I > 2.00r(I)), Rw = 0.1786 (I > 2.00r(I)), GOF = 0.875, Flack
parameter = 0.019(13). Crystallographic data (excluding structure factors) for
the structure of (R,S)-1a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers CCDC
703258 and can be obtained free of charge via the Internet at http://
www.ccdc.cam.ac.uk/data_request/cif.
9. This was also an advantageous point of the present work because we could not
previously determine the absolute configuration of the chiral spiro hybrid
ligands, see Ref. 5.
10. Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466.
11. Coulson, D. R. Inorg. Synth. 1972, 13, 121.